EPTIFIBATIDE: 462 Adverse Event Reports & Safety Profile

Eptifibatide is a cyclic heptapeptide containing 6 amino acids and 1 mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N 6 -(aminoiminomethyl)-N 2 -(3-mercapto-1-oxopropyl)-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation. The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is: Eptifibatide Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C 35 H 49 N 11 O 9 S 2 and a molecular weight of 831.96. Eptifibatide injection is a refrigerated, premixed, sterile, non-pyrogenic single-dose solution packaged in the Galaxy container.

The

100 mL container consists of 0.75 mg/mL of eptifibatide. The container also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.

The

Galaxy container is fabricated from a specially designed multilayered plastic. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

Eptifibatide Chemical

Structure

AND USAGE Eptifibatide injection is a platelet aggregation inhibitor indicated for:

• Treatment of acute coronary syndrome (ACS) managed medically or with percutaneous coronary intervention (PCI) ( 1.1 )
• Treatment of patients undergoing PCI (including intracoronary stenting) ( 1.2 )

1.1 Acute Coronary Syndrome (ACS) Eptifibatide injection is indicated to decrease the rate of a combined endpoint of death or new myocardial infarction (MI) in patients with ACS (unstable angina [UA]/non-ST- elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI).

1.2 Percutaneous Coronary Intervention (PCI) Eptifibatide injection is indicated to decrease the rate of a combined endpoint of death, new MI, or need for urgent intervention in patients undergoing PCI, including those undergoing intracoronary stenting <span class="opacity-50 text-xs">[see Clinical Studies (14.1 , 14.2) ]</span> .

AND ADMINISTRATION Eptifibatide injection in Galaxy container is for intravenous infusion only, not for intravenous bolus use. Before infusion of eptifibatide injection, the following laboratory tests should be performed to identify pre-existing hemostatic abnormalities: hematocrit or hemoglobin, platelet count, serum creatinine, and PT/aPTT. In patients undergoing PCI, the activated clotting time (ACT) should also be measured. The activated partial thromboplastin time (aPTT) should be maintained between 50 and 70 seconds unless PCI is to be performed. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT. Eptifibatide injection in Galaxy container is for intravenous infusion only, not for intravenous bolus use. ACS or PCI: 180 mcg/kg IV bolus as soon as possible after diagnosis followed by infusion at 2 mcg/kg/min. (2.1 , 2.2) PCI: Add a second 180 mcg/kg bolus at 10 minutes. ( 2.2 ) In patients with creatinine clearance less than 50 mL/min, reduce the infusion to 1 mcg/kg/min. (2.1, 2.2 , 2.3 )

2.1 Dosage in Acute Coronary Syndrome (ACS)

Indication Normal Renal Function Creatinine

Clearance less than 50 mL/min Patients with ACS 180 mcg/kg intravenous (IV) bolus as soon as possible after diagnosis, followed by continuous infusion of 2 mcg/kg/min 180 mcg/kg IV bolus as soon as possible after diagnosis, followed by continuous infusion of 1 mcg/kg/min

• Infusion should continue until hospital discharge or initiation of coronary artery bypass graft surgery (CABG), up to 72 hours
• If a patient is to undergo PCI, the infusion should be continued until hospital discharge or for up to 18 to 24 hours after the procedure, whichever comes first, allowing for up to 96 hours of therapy
• Aspirin, 160 to 325 mg, should be given daily Eptifibatide injection should be given concomitantly with heparin dosed to achieve the following parameters: During Medical Management : Target aPTT 50 to 70 seconds
• If weight greater than or equal to 70 kg, 5000-unit bolus followed by infusion of 1000 units/h.
• If weight less than 70 kg, 60-units/kg bolus followed by infusion of 12 units/kg/h. During PCI : Target ACT 200 to 300 seconds
• If heparin is initiated prior to PCI, additional boluses during PCI to maintain an ACT target of 200 to 300 seconds.
• Heparin infusion after the PCI is discouraged.

2.2 Dosage in Percutaneous Coronary Intervention (PCI)

Indication Normal Renal Function Creatinine

Clearance less than 50 mL/min Patients with PCI 180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of 2 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus) 180 mcg/kg IV bolus immediately before PCI followed by continuous infusion of 1 mcg/kg/min and a second bolus of 180 mcg/kg (given 10 minutes after the first bolus)

• Infusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended.
• In patients who undergo CABG surgery, eptifibatide injection infusion should be discontinued prior to surgery.
• Aspirin, 160 to 325 mg, should be given 1 to 24 hours prior to PCI and daily thereafter.
• Eptifibatide injection should be given concomitantly with heparin to achieve a target ACT of 200 to 300 seconds.

Administer

60-units/kg bolus initially in patients not treated with heparin within 6 hours prior to PCI.

• Additional boluses during PCI to maintain ACT within target.
• Heparin infusion after the PCI is strongly discouraged. Patients requiring thrombolytic therapy should discontinue eptifibatide injection.

2.3 Important Administration Instructions 1. Inspect eptifibatide injection for particulate matter and discoloration prior to administration. Use only if solution is clear and container and seals are intact. Check for minute leaks prior to use by squeezing bag firmly. If leaks are found, discard solution as sterility may be impaired. If the administration port protector is damaged, detached or not present, discard the container as the solution path sterility may be compromised. 2. Do not use Galaxy containers in series connections. Such use would result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. 3. This premixed solution is for intravenous infusion only, no further dilution is required.

Not For Intravenous Bolus

Use. 4. Do not introduce supplemental medication or additives into the Galaxy container. 5. May administer eptifibatide injection in the same intravenous line as alteplase, atropine, dobutamine, heparin, lidocaine, meperidine, metoprolol, midazolam, morphine, nitroglycerin, or verapamil. Do not administer eptifibatide injection through the same intravenous line as furosemide. 6. May administer eptifibatide injection in the same IV line with 0.9% NaCl or 0.9% NaCl/5% dextrose. With either vehicle, the infusion may also contain up to 60 mEq/L of potassium chloride. 7. Withdraw the bolus dose(s) of eptifibatide injection from the 10-mL vial into a syringe. Administer the bolus dose(s) by IV push. 8. Immediately following the bolus dose administration, initiate a continuous infusion of eptifibatide injection. When using an intravenous infusion pump, administer eptifibatide injection undiluted directly from the 100-mL Galaxy container. 9. The premixed Galaxy container is for single-dose only, discard any unused portion. Administer eptifibatide injection by volume according to patient weight (see Table 1).

Table

1: Eptifibatide Injection Dosing Charts by Weight Patient Weight 180-mcg/kg Bolus Volume 2-mcg/kg/min Infusion Volume (CrCl greater than or equal to 50 mL/min) 1-mcg/kg/min Infusion Volume (CrCl less than 50 mL/min) (kg) (lb) (from 2 mg/mL vial) (from 0.75-mg/mL 100-mL Galaxy container) (from 0.75-mg/mL 100-mL Galaxy container) 37-41 81-91 3.4 mL 6 mL/h 3 mL/h 42-46 92-102 4 mL 7 mL/h 3.5 mL/h 47-53 103-117 4.5 mL 8 mL/h 4 mL/h 54-59 118-130 5 mL 9 mL/h 4.5 mL/h 60-65 131-143 5.6 mL 10 mL/h 5 mL/h 66-71 144-157 6.2 mL 11 mL/h 5.5 mL/h 72-78 158-172 6.8 mL 12 mL/h 6 mL/h 79-84 173-185 7.3 mL 13 mL/h 6.5 mL/h 85-90 186-198 7.9 mL 14 mL/h 7 mL/h 91-96 199-212 8.5 mL 15 mL/h 7.5 mL/h 97-103 213-227 9 mL 16 mL/h 8 mL/h 104-109 228-240 9.5 mL 17 mL/h 8.5 mL/h 110-115 241-253 10.2 mL 18 mL/h 9 mL/h 116-121 254-267 10.7 mL 19 mL/h 9.5 mL/h >121 >267 11.3 mL 20 mL/h 10 mL/h

Treatment with eptifibatide is contraindicated in patients with:

• A history of bleeding diathesis, or evidence of active abnormal bleeding within the previous 30 days
• Severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >110 mm Hg) not adequately controlled on antihypertensive therapy
• Major surgery within the preceding 6 weeks
• History of stroke within 30 days or any history of hemorrhagic stroke
• Current or planned administration of another parenteral GP IIb/IIIa inhibitor
• Dependency on renal dialysis
• Hypersensitivity to eptifibatide or any component of the product (hypersensitivity reactions that occurred included anaphylaxis and urticaria).
• Bleeding diathesis or bleeding within the previous 30 days ( 4 )
• Severe uncontrolled hypertension ( 4 )
• Major surgery within the preceding 6 weeks ( 4 )
• Stroke within 30 days or any history of hemorrhagic stroke ( 4 )
• Coadministration of another parenteral GP IIb/IIIa inhibitor ( 4 )
• Dependency on renal dialysis ( 4 )
• Known hypersensitivity to any component of the product ( 4 )

REACTIONS The following serious adverse reaction is also discussed elsewhere in the labeling:

• Bleeding [see Contraindications (4) and Warnings and Precautions (5.1) ] Bleeding and hypotension are the most commonly reported adverse reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 16,782 patients were treated in the Phase III clinical trials (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Eptifibatide Therapy (PURSUET), Enhanced Suppression of the Platelet IIb/IIIa Receptor with Eptifibatide Therapy (ESPRET), and Eptifibatide to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II (EMPACT II)) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> .

These

16,782 patients had a mean age of 62 years (range: 20 to 94 years). Eighty-nine percent of the patients were Caucasian, with the remainder being predominantly Black (5%) and Hispanic (5%). Sixty-eight percent were men. Because of the different regimens used in PURSUET, EMPACT II, and ESPRET, data from the 3 studies were not pooled. Bleeding and hypotension were the most commonly reported adverse reactions (incidence ≥5% and greater than placebo) in the eptifibatide controlled clinical trial database.

Bleeding

The incidence of bleeding and transfusions in the PURSUET and ESPRET studies are shown in Table 2. Bleeding was classified as major or minor by the criteria of the TIMI study group. Major bleeding consisted of intracranial hemorrhage and other bleeding that led to decreases in hemoglobin greater than 5 g/dL. Minor bleeding included spontaneous gross hematuria, spontaneous hematemesis, other observed blood loss with a hemoglobin decrease of more than 3 g/dL, and other hemoglobin decreases that were greater than 4 g/dL but less than 5 g/dL. In patients who received transfusions, the corresponding loss in hemoglobin was estimated through an adaptation of the method of Landefeld et al.

Table

2: Bleeding and Transfusions in the PURSUET and ESPRET Studies PURSUET (ACS) Placebo n (%)

Eptifibatide Injection

180/2 n (%)

Patients

4696 4679 Major bleeding* Minor bleeding* Requiring transfusions † 425 (9.3%) 347 (7.6%) 490 (10.4%) 498 (10.8%) 604 (13.1%) 601 (12.8%) ESPRET (PCI) Placebo n (%)

Eptifibatide Injection

180/2/180 n (%)

Patients

1024 1040 Major bleeding* Minor bleeding* Requiring transfusions † 4 (0.4%) 18 (2%) 11 (1.1%) 13 (1.3%) 29 (3%) 16 (1.5%) Note: Denominator is based on patients for whom data are available. * For major and minor bleeding, patients are counted only once according to the most severe classification. † Includes transfusions of whole blood, packed red blood cells, fresh frozen plasma, cryoprecipitate, platelets, and autotransfusion during the initial hospitalization. The majority of major bleeding reactions in the ESPRET study occurred at the vascular access site (1 and 8 patients, or 0.1% and 0.8% in the placebo and eptifibatide groups, respectively). Bleeding at “other” locations occurred in 0.2% and 0.4% of patients, respectively. In the PURSUET study, the greatest increase in major bleeding in eptifibatide-treated patients compared to placebo-treated patients was also associated with bleeding at the femoral artery access site (2.8% versus 1.3%). Oropharyngeal (primarily gingival), genitourinary, gastrointestinal, and retroperitoneal bleeding were also seen more commonly in eptifibatide-treated patients compared to placebo-treated patients. Among patients experiencing a major bleed in the EMPACT II study, an increase in bleeding on eptifibatide versus placebo was observed only for the femoral artery access site (3.2% versus 2.8%).

Table

3 displays the incidence of TIMI major bleeding according to the cardiac procedures carried out in the PURSUET study. The most common bleeding complications were related to cardiac revascularization (CABG-related or femoral artery access site bleeding). A corresponding table for ESPRET is not presented, as every patient underwent PCI in the ESPRET study and only 11 patients underwent CABG.

Table

3: Major Bleeding by Procedures in the PURSUET Study Placebo n (%)

Eptifibatide

180/2 n (%)

Patients

4577 4604 Overall incidence of major bleeding 425 (9.3%) 498 (10.8%) Breakdown by procedure: CABG 375 (8.2%) 377 (8.2%) Angioplasty without CABG 27 (0.6%) 64 (1.4%) Angiography without angioplasty or CABG 11 (0.2%) 29 (0.6%) Medical therapy only 12 (0.3%) 28 (0.6%) Note: Denominators are based on the total number of patients whose TIMI classification was resolved. In the PURSUET and ESPRET studies, the risk of major bleeding with eptifibatide increased as patient weight decreased. This relationship was most apparent for patients weighing less than 70 kg. Bleeding resulting in discontinuation of the study drug was more frequent among patients receiving eptifibatide than placebo (4.6% versus 0.9% in ESPRET, 8% versus 1% in PURSUET, 3.5% versus 1.9% in EMPACT II).

Intracranial

Hemorrhage and Stroke Intracranial hemorrhage was rare in the PURSUET, EMPACT II, and ESPRET clinical studies. In the PURSUET study, 3 patients in the placebo group, 1 patient in the group treated with eptifibatide 180/1.3, and 5 patients in the group treated with eptifibatide 180/2 experienced a hemorrhagic stroke. The overall incidence of stroke was 0.5% in patients receiving eptifibatide 180/1.3, 0.7% in patients receiving eptifibatide 180/2, and 0.8% in placebo patients. In the EMPACT II study, intracranial hemorrhage was experienced by 1 patient treated with eptifibatide 135/0.5, 2 patients treated with eptifibatide 135/0.75, and 2 patients in the placebo group. The overall incidence of stroke was 0.5% in patients receiving 135/0.5 eptifibatide, 0.7% in patients receiving eptifibatide 135/0.75, and 0.7% in the placebo group. In the ESPRET study, there were 3 hemorrhagic strokes, 1 in the placebo group and 2 in the eptifibatide group. In addition there was 1 case of cerebral infarction in the eptifibatide group.

Immunogenicity/Thrombocytopenia

The potential for development of antibodies to eptifibatide has been studied in 433 subjects. Eptifibatide was nonantigenic in 412 patients receiving a single administration of eptifibatide (135 mcg/kg bolus followed by a continuous infusion of either 0.5 mcg/kg/min or 0.75 mcg/kg/min), and in 21 subjects to whom eptifibatide (135 mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min) was administered twice, 28 days apart. In both cases, plasma for antibody detection was collected approximately 30 days after each dose. The development of antibodies to eptifibatide at higher doses has not been evaluated. In patients with suspected eptifibatide-related immune-mediated thrombocytopenia, IgG antibodies that react with the GP IIb/IIIa complex were identified in the presence of eptifibatide and in eptifibatide injection-naïve patients. These findings suggest acute thrombocytopenia after the administration of eptifibatide can develop as a result of naturally occurring drug-dependent antibodies or those induced by prior exposure to eptifibatide. Similar antibodies were identified with other GP IIb/IIIa ligand-mimetic agents. Immune-mediated thrombocytopenia with eptifibatide may be associated with hypotension and/or other signs of hypersensitivity. In the PURSUET and EMPACT II studies, the incidence of thrombocytopenia (<100,000/mm 3 or ≥50% reduction from baseline) and the incidence of platelet transfusions were similar between patients treated with eptifibatide and placebo. In the ESPRET study, the incidence was 0.6% in the placebo group and 1.2% in the eptifibatide group.

Other Adverse

Reactions In the PURSUET and ESPRET studies, the incidence of serious nonbleeding adverse reactions was similar in patients receiving placebo or eptifibatide (19% and 19%, respectively, in PURSUET; 6% and 7%, respectively, in ESPRET). In PURSUET, the only serious nonbleeding adverse reaction that occurred at a rate of at least 1% and was more common with eptifibatide than placebo (7% versus 6%) was hypotension. Most of the serious nonbleeding adverse reactions consisted of cardiovascular reactions typical of a UA population. In the EMPACT II study, serious nonbleeding adverse reactions that occurred in greater than 1% of patients were uncommon and similar in incidence between placebo- and eptifibatide-treated patients. Discontinuation of study drug due to adverse reactions other than bleeding was uncommon in the PURSUET, EMPACT II, and ESPRIT studies, with no single reaction occurring in >0.5% of the study population (except for “other” in the ESPRET study).

6.2 Postmarketing Experience The following adverse reactions have been reported in post-approval use of eptifibatide in combination with heparin and aspirin. Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: cerebral, GI, and pulmonary hemorrhage. Fatal bleeding reactions have been reported. Acute profound thrombocytopenia, as well as immune-mediated thrombocytopenia, have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

AND PRECAUTIONS Eptifibatide injection can cause serious bleeding. If bleeding cannot be controlled, discontinue eptifibatide injection immediately. Minimize vascular and other traumas. If heparin is given concomitantly, monitor aPTT or ACT. ( 5.1 ) Thrombocytopenia: Discontinue eptifibatide injection and heparin. Monitor and treat condition appropriately. ( 5.2 )

5.1 Bleeding Bleeding is the most common complication encountered during eptifibatide injection therapy. Administration of eptifibatide injection is associated with an increase in major and minor bleeding, as classified by the criteria of the Thrombolysis in Myocardial Infarction Study group (TIMI) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Most major bleeding associated with eptifibatide injection has been at the arterial access site for cardiac catheterization or from the gastrointestinal or genitourinary tract. Minimize the use of arterial and venous punctures, intramuscular injections, and the use of urinary catheters, nasotracheal intubation, and nasogastric tubes. When obtaining intravenous access, avoid non-compressible sites (e.g., subclavian or jugular veins). Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents Risk factors for bleeding include older age, a history of bleeding disorders, and concomitant use of drugs that increase the risk of bleeding (thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs, and P2Y 12 inhibitors). Concomitant treatment with other inhibitors of platelet receptor glycoprotein (GP) IIb/IIIa should be avoided. In patients treated with heparin, bleeding can be minimized by close monitoring of the aPTT and ACT <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 )]</span> . Care of the Femoral Artery Access Site in Patients Undergoing Percutaneous Coronary Intervention (PCI) In patients undergoing PCI, treatment with eptifibatide injection is associated with an increase in major and minor bleeding at the site of arterial sheath placement. After PCI, eptifibatide infusion should be continued until hospital discharge or up to 18 to 24 hours, whichever comes first. Heparin use is discouraged after the PCI procedure. Early sheath removal is encouraged while eptifibatide injection is being infused. Prior to removing the sheath, it is recommended that heparin be discontinued for 3 to 4 hours and an aPTT of &lt;45 seconds or ACT &lt;150 seconds be achieved. In any case, both heparin and eptifibatide injection should be discontinued and sheath hemostasis should be achieved at least 2 to 4 hours before hospital discharge. If bleeding at access site cannot be controlled with pressure, infusion of eptifibatide injection and heparin should be discontinued immediately.

5.2 Thrombocytopenia There have been reports of acute, profound thrombocytopenia (immune-mediated and non-immune mediated) with eptifibatide injection. In the event of acute profound thrombocytopenia or a confirmed platelet decrease to &lt;100,000/mm 3 , discontinue eptifibatide injection and heparin (unfractionated or low-molecular weight). Monitor serial platelet counts, assess the presence of drug-dependent antibodies, and treat as appropriate <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . There has been no clinical experience with eptifibatide injection initiated in patients with a baseline platelet count &lt;100,000/mm 3 . If a patient with low platelet counts is receiving eptifibatide injection, their platelet count should be monitored closely.

INTERACTIONS

• Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Avoid concomitant use with other glycoprotein (GP) IIb/IIIa inhibitors. ( 7.1 )

7.1 Use of Thrombolytics, Anticoagulants, and Other Antiplatelet Agents Coadministration of antiplatelet agents, thrombolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. Concomitant treatment with other inhibitors of platelet receptor GP IIb/IIIa should be avoided.